| Autor: |
Wang, Xuesong, Cottrell, Christopher A., Hu, Xiaozhen, Ray, Rashmi, Bottermann, Maria, Villavicencio, Paula Maldonado, Yan, Yu, Xie, Zhenfei, Warner, John E., Ellis-Pugh, Jordan Renae, Kalyuzhniy, Oleksandr, Liguori, Alessia, Willis, Jordan R., Menis, Sergey, Rämisch, Sebastian, Eskandarzadeh, Saman, Kubitz, Michael, Tingle, Ryan, Phelps, Nicole, Groschel, Bettina |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 95, p1-15, 15p |
| Abstrakt: |
Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle–encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway. Editor's summary: Germline-targeting (GT) vaccination is a promising approach to elicit broadly neutralizing antibodies against conserved sites within the variable HIV envelope (Env) protein. GT vaccination uses an initial "prime" to activate B cells expressing anti-Env bnAb precursors and recruit them into germinal centers. Env-like immunogens are then administered as a "boost," driving increased antibody potency and breadth. Wang et al. characterize mRNA-LNP vaccination with an Env immunogen (eOD-GT8 60mer) as well as three different boost-phase immunogens in mice that had received an adoptive transfer of three distinct knock-in B cell lines, mimicking the competition that occurs in humans between anti-Env precursors. All three precursor lineages showed noncompetitive priming by the same immunogen but disparate responses at the boost stage, providing an important proof of concept for current approaches to GT vaccination. —Seth Thomas Scanlon [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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